Thrombin inhibitors

ABSTRACT

Thrombin inhibitors of the formula ##STR1## where R 1 , A, B and D have the meaning indicated in the description, and intermediates for the preparation thereof are described. 
     The compounds I are suitable for controlling diseases.

This application is a 371 of PCT/EP96/00472 filed Feb. 6, 1996.

The present invention relates to p-amidinobenzylamides of peptides withN-terminal sulfonyl or aminosulfonyl radicals, to the preparationthereof and to the use thereof as thrombin inhibitors.

EP 601 459, EP 672 658, WO 94/29336 and WO 95/23609 describe peptidethrombin inhibitors.

The present invention relates to thrombin inhibitors of the formula I##STR2## and the stereoisomers thereof and the salts thereof withphysiologically tolerated acids, where the amidine functionality can bein mono- or diprotected form and in which the substituents have thefollowing meanings:

R¹ OH, C₁ -C₂₀ -alkyl, C₁ -C₃ -fluoroalkyl, C₃ -C₈ -cycloalkyl, aryl-C₁-C₁₀ -alkyl, aryl, hetaryl, R² OOC--(CH₂)_(n) or R³ R² N, where R² andR³ are identical or different and are hydrogen, C₁ -C₁₀ -alkyl, aryl,aryl-C₁ -C₁₀ -alkyl or together are a C₂ -C₇ -alkylene chain to which anaryl or hetaryl radical can be fused or which can contain a hetero atom(O, S, NH or substituted N), and n is 1, 2, 3 or 4,

A: an α-amino acid residue of the formula II ##STR3## where R⁴ ishydrogen, C₁ -C₈ -alkyl, C₃ -C₇ -cycloalkyl, aryl or aryl-C₁ -C₃ -alkyl,

R⁵ is hydrogen, C₁ -C₈ -alkyl, C₃ -C₇ -cycloalkyl or C₃ -C₇-cycloalkyl-CH₂ --, it being possible for a CH₂ group in the ring to bereplaced by O, S, NR⁶, or bicycloalkyl-(CH₂)₀,1 sic!,adamantyl-(CH₂)₀₋₁, (CH₃)₃ Si--C₁ -C₄ -alkyl, aryl or aryl-C₁ -C₃-alkyl, hetaryl or hetaryl-C₁ -C₃ -alkyl, if R⁴ is H, a C₁ -C₈ -alkylradical in which a hydrogen atom is replaced by SR⁶, OR⁶, CO--OR⁶ (R⁶=hydrogen, C₁ -C₈ -alkyl or aryl-C₁ -C₃ -alkyl) or CONR⁷ R⁸ (R⁷, R⁸ areidentical or different and are H, C₁ -C₄ -alkyl, C₃ -C₇ -cycloalkyl ortogether are a C₃ -C₆ -alkylene chain), or

R⁴ and R⁵ together are a C₂ -C₆ -alkylene chain which may contain afused-on aryl radical,

B: a cyclic α-amino acid residue of the formula III ##STR4## where m is2, 3 or 4, and a hydrogen on the ring can be replaced by a hydroxyl orC₁ -C₃ -alkyl group and, if m is 3 or 4, a CH₂ group in the ring can bereplaced by oxygen, sulfur, NH or N--C₁ -C₄ -alkyl and/or two vicinalhydrogen atoms can be replaced by a double bond or by a fused-onaromatic system or a methylene chain with 4-6 carbon atoms,

D: a structural fragment of the formula IV, V or VI ##STR5## where R⁹ isF, Cl, Br, NO₂, R¹⁵ O, R¹⁵ OOC, R¹⁵ OCH₂, R¹⁵ NH, R¹⁵ CONH, R¹⁵ NH--COor R¹⁵ OOCCH₂ O, where R¹⁵ is H, C₁ -C₆ -alkyl, benzyl or phenyl,

R¹⁰, R¹¹ are H, C₁ -C₄ -alkyl or R¹⁵ O, where R⁹ and R¹⁰ or R¹¹ maytogether form a fused-on phenylene ring or an alkylene chain consistingof 3 to 5 carbon atoms, in which one or two carbon atoms can be replacedby oxygen,

R¹² is H or C₁ -C₄ -alkyl,

R¹³ is C₁ -C₄ -alkyl, phenyl-C₁ -C₄ -alkyl, R¹⁵ CO, CF₃ CO, C₂ F₅ CO,R¹⁵ OCH₂, R¹⁵ OOC, R¹⁵ OCH₂ CO, R¹⁵ OOCCO or R¹⁵ NHCOCO,

R¹⁴ is H, C₁ -C₄ -alkyl, F, Cl, Br, NO₂, R¹⁵ O, R¹⁵ OOC, R¹⁵ OCH₂, R¹⁵NH, R¹⁵ CONH, R¹⁵ NH--CO or R¹⁵ OOCCH₂ O, and

W, X, Y, Z are CH or N, but at least one of the radicals W, X, Y or Z isN and the ring in VI can be substituted by 1 or 2 of the followingradicals: C₁ -C₄ -alkyl, OH, O--C₁ -C₄ -alkyl, CF₃, F, Cl, Br, S--C₁ -C₄-alkyl, O(CH₂)_(n) COOR⁶ (n=1-4).

The term "aryl" everywhere means mono- or bicyclic aromatic groups whichcontain 6 to 10 carbon atoms in the ring system, eg. phenyl or naphthyl,and which can be provided with up to three identical or differentsubstituents.

The term "hetaryl" everywhere refers to 5- or 6-membered aromatic ringswhich may contain 1 or 2 hetero atoms such as N, O or S and to which anaryl ring, for example a phenyl ring, can be fused.

The term "cycloalkyl" means saturated cyclic hydrocarbon radicals with 3to 7 carbon atoms, eg. cyclopentyl, cyclohexyl, cycloheptyl, it beingpossible for the rings to be substituted by halogen, C₁ -C₄ -alkyl andO--C₁ -C₄ -alkyl.

The following compound groups Ia to Ig are preferred: ##STR6##

Herein, the substituents R and the fragments A and B have the followingmeanings:

R¹ : OH, C₁ -C₁₀ -alkyl, CF₃ CH₂, phenyl, naphthyl, phenyl-C₁ -C₄ -alkyl(especially benzyl and phenethyl), naphthyl-C₁ -C₄ -alkyl, pyridyl,isoquinolyl, NH₂, C₁ -C₄ -mono- and dialkylamino, piperidinyl.

A: glycine, alanine, valine, leucine, isoleucine, phenyl- andcyclohexylglycine, phenyl- and cyclohexylalanine,tetrahydropyranylglycine, tetrahydropyranylvaline,α-methylcyclohexylalanine, diphenyl- and dicyclohexylalanine, it beingpossible for phenyl rings present in the residues to be substituted byup to three identical or different C₁ -C₄ -alkyl, O--C₁ -C₄ -alkyl, OH,F, Cl or COOR⁶ radicals, aspartic acid, glutamic acid, asparagine,glutamine, the nitrogen atom possibly carrying, if required, one or twoalkyl groups or being part of a C₄ -C₈ -ring, serine, homoserine,threonine, it being possible for the carboxyl or hydroxyl group to beesterified or etherified by a C₁ -C₈ -alkyl radical.

The amino acids A preferably have the D configuration. ##STR7##

The B fragments preferably have the L configuration.

R⁹ : is Cl, Br, NO₂, R¹⁵ O, R¹⁵ OOC, R¹⁵ OCH₂, R¹⁵ NH, R¹⁵ CONH or R¹⁵OOCCH₂ O, where R¹⁵ is H, C₁ -C₆ -alkyl, benzyl or phenyl,

R¹⁰ : is H, C₁ -C₄ -alkyl or R¹⁵ O.

Particularly preferred substituents R and fragments A and B have thefollowing meanings:

R¹ : HO, CH₃, CH₃ -CH₂, CH₃ --(CH₂)₃, CF₃ --CH₂, phenyl, benzyl,phenethyl, pyridyl, (CH₃)₂ N, CH₃ --NH, NH₂ and piperidinyl,

A: cyclohexylglycine or cyclohexylalanine, tetrahydro-4-pyranylglycine,tetrahydro-4-pyranylvaline, dicyclohexyl- or diphenylalanine orphenylalanine, it being possible for the phenyl rings to be substitutedby up to 3 identical or different CH₃ O, CH₃, HO, F or Cl radicals,serine or tert-butylserine.

The amino acids preferably have the D configuration. ##STR8##

The B fragments preferably have the L configuration.

R⁹ : Cl, CH₃ O or HO

R¹⁰ : H, CH₃ or CH₃ O ##STR9##

The meanings of the substituent R¹, the fragments A and B and X hereinare as follows:

R¹ : OH, C₁ -C₁₀ -alkyl, CF₃ CH₂, phenyl, naphthyl, phenyl-C₁ -C₄ -alkyl(especially benzyl and phenethyl), naphthyl-C₁ -C₄ -alkyl, pyridyl,isoquinolyl, NH₂, C₁ -C₄ -mono- or dialkylamino, piperidinyl.

A: glycine, alanine, valine, leucine, isoleucine, phenyl- orcyclohexylglycine, phenyl- or cyclohexylalanine,tetrahydropyranylglycine, tetrahydropyranylvaline, diphenyl- ordicyclohexylalanine, it being possible for phenyl rings present in theresidues to be substituted by up to three identical or different C₁ -C₄-alkyl, O--C₁ -C₄ -alkyl, OH, F, Cl or COOR⁶ radicals, aspartic acid,glutamic acid, asparagine, glutamine, the nitrogen atom possiblycarrying, if required, one or two alkyl groups or being part of a C₄ -C₈ring, serine, homoserine, threonine, it being possible for the carboxylor hydroxyl group to be esterified or etherified by a C₁ -C₈ -alkylradical.

The amino acids A preferably have the D configuration. ##STR10##

The B fragments preferably have the L configuration.

X: CH or N.

Particularly preferred meanings for the substituent R¹, the fragments Aand B and X are as follows:

R¹ : HO, CH₃, CH₃ --CH₂, CH₃ --(CH₂)₃, CF₃ --CH₂, phenyl, benzyl,phenethyl, pyridyl, (CH₃)₂ N, CH₃ --NH, NH₂ and piperidinyl,

A: cyclohexylglycine or cyclohexylanine sic!,tetrahydro-4-pyranylglycine, tetrahydro-4-pyranylvaline, dicyclohexyl-or diphenylalanine or phenylalanine, it being possible for the phenylrings to be substituted by up to 3 identical or different CH₃ O, CH₃,HO, F or Cl radicals, serine or tert-butylserine.

The amino acids preferably have the D configuration. ##STR11##

The B fragments preferably have the L configuration.

X: CH or N

or

the substituents R, the fragments A and B and X in the compounds Ic, Idand Ie have the following meanings:

R¹ : OH, C₁ -C₁₀ -alkyl, CF₃ CH₂, phenyl, naphthyl, phenyl-C₁ -C₄ -alkyl(especially benzyl and phenethyl), naphthyl-C₁ -C₄ -alkyl, pyridyl,isoquinolyl, NH₂, C₁ -C₄ -mono- or dialkylamino, piperidinyl.

A: cyclohexylglycine or cyclohexylanine sic!, tetrahydropyranylglycine,tetrahydropyranylvaline, diphenyl- or dicyclohexylalanine, phenylalaninewhich is substituted by 2 or 3 identical or different radicals from thegroup of CH₃ O, CH₃, HO, F or Cl, or serine or tert-butylserine. Theamino acids A preferably have the D configuration. ##STR12##

The B fragment preferably has the L configuration.

X: CH or N ##STR13##

The substituents R, the fragments A and B and X herein have thefollowing meanings:

R¹ : OH, C₁ -C₁₀ -alkyl, CF₃ CH₂, phenyl, naphthyl, phenyl-C₁ -C₄ -alkyl(especially benzyl and phenethyl), naphthyl-C₁ -C₄ -alkyl, pyridyl,isoquinolyl, NH₂, C₁ -C₄ -mono- or dialkylamino, piperidinyl.

A: glycine, alanine, valine, leucine, isoleucine, phenyl- orcyclohexylglycine, phenyl- or cyclohexylalanine,tetrahydro-4-pyranylglycine, tetrahydro-4-pyranylvaline,α-methylcyclohexylalamine sic!, diphenyl- or dicyclohexylalanine, itbeing possible for phenyl rings present in the residues to besubstituted by up to three identical or different C₁ -C₄ -alkyl, O--C₁-C₄ -alkyl, OH, F, Cl or COOR⁶ radicals, aspartic acid, glutamic acid,asparagine, glutamine, the nitrogen atom possibly carrying, if required,one or two alkyl groups or being part of a C₄ -C₈ ring, serine,homoserine, threonine, it being possible for the carboxyl or hydroxylgroup to be esterified or etherified by a C₁ -C₈ -alkyl radical. Theamino acids preferably have the D configuration. ##STR14##

The B fragments are preferably in the L configuration.

R': CH₃ or CH₃ O

X: CH or N

The following substances may be specifically mentioned:

MeSO₂ -(D)-α-Me-Cha-Pro-NH-(2-MeO)-4-amb

EtSO₂ -(D,L)-Cog-Pro-NH-(2-MeO)-4-amb

EtSO₂ -D-(3,4-Dimethoxy)Phe-Pro-NH-(2-MeO)-4-amb

MeSO₂ -(D,L)-(1-Tetralinyl)Gly-Pro-NH-(2-MeO)-4-amb

MeSO₂ -(D,L)-Dpa-Pro-NH-(2-MeO)-4-amb

MeSO₂ -(D,L)-(5-Dibenzosuberyl)Gly-Pro-NH-(2-MeO)-4-amb

EtSO₂ -D-(4-Methoxy)Phe-Pro-NH-(2 MeO)-4-amb

MeSO₂ -(D,L)-(3,4,5-Trimethoxy)Phe-Pro-NH-(2-MeO)-4-amb

CF₃ SO₂ -D-(4-Chloro)Phe-Pro-NH-(2-MeO)-4-amb

CF₃ SO₂ -(D,L)-(Me₃ Si)Ala-Pro-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Chg-Pro-NH-(2-MeO)-4-amb

CF₃ CH₂ SO₂ -(D)-Chg-Pro-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Phe-Aze-NH-(2-MeO)-4-amb

MeSO₂ -(D)-(tert-Butyl)Ser-Pro-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Cha-Pro-NH-(2-MeO)-4-amb

Bz-SO₂ -(D)-Cha-Pro-NH-(2-MeO)-4-amb

n-Bu-SO₂ -(D)-Cha-Pro-NH-(2-MeO)-4-amb

HO--SO₂ -(D)-Chg-Pro-NH-(2-MeO)-4-amb

H₂ N--SO₂ -(D)-Chg-Pro-NH-(2-MeO)-4-amb

H₂ N--SO₂ -(D)-Chg-Pro-NH-(2-MeO)-4-amb

HOOC--CH₂ --CH₂ --SO₂ -(D)-Chg-Pro-NH-(2-MeO)-4-amb

2-Naphth.-SO₂ -(D)-Phe-Pro-NH-(2-MeO)-4-amb

MeSO₂ -(D,L)-(β-Phenyl)Pro-Pro-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Chg-Aze-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Chg-Pic-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Chg-Hyp-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Chg-Pyr-NH-(2-MeO)-4-amb

EtSO₂ -(D)-Chg-(N-cyclopropyl)Gly-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Chg-1-Tic-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Chg-2-Ind-NH-(2-MeO)-4-amb

MeSO₂ -(D)-Chg-2-Phi-NH-(2-MeO)-4-amb

EtSO₂ -(D)-Chg-(Cyclo)Leu-NH-(2-MeO)-4-amb

Pro-SO₂ -(D)-Chg-Pro-NH-(2-iPrO)-4-amb

Ph-SO₂ -(D)-Chg-Pro-NH-(2-OH)-4-amb

MeSO₂ -(D)-Chg-Pro-NH-(2-OCH₂ -COOH)-4-amb

MeSO₂ -(D)-Chg-Pro-NH-(2-NH-COMe)-4-amb

MeSO₂ -(D)-Chg-Pro-NH-(2-NH₂)-4-amb

EtSO₂ -(D)-Chg-Pro-NH-(2-COOH)-4-amb

MeSO₂ -(D)-Chg-Pro-NH-(2-COOMe)-4-amb

MeSO₂ -(D)-Chg-Pro-NH-(2-CH₂ OH)-4-amb

EtSO₂ - (D) -Chg-Pro-NH-(2-Cl)-4-amb

HO--SO₂ -(D)-Chg-Pro-NH-(2-Br)-4-amb

H₂ N--SO₂ -(D)-Chg-Pro-NH-(2,6-Dimethoxy)-4-amb

MeSO₂ -(D)-Chg-Pro-NH-(2,3-Dimethoxy)-4-amb

EtSO₂ -(D)-Chg-Pro-NH-(3-MeO)-4-amb

HOSO₂ -(D)-Chg-Pro-NH-(3-OH)-4-amb

CF₃ SO₂ -(D)-Chg-Pro-NH-(3-iPrO)-4-amb

MeSO₂ -(D)-Chg-Pro-NH-(3-Cl)-4-amb

EtSO₂ -(D)-Chg-Pro-NH-(4-am)-napme

MeSO₂ -(D)-Chg-Pro-NH-4-amb(Me)

MeSO₂ -(D)-Chg-Pro-NH-4-amb(COOH)

MeSO₂ -(D)-Chg-Pro-NH-4-amb(COOMe)

MeSO₂ -(D)-Phe-Pro-NH-4-amb(CH₂ OH)

MeSO₂ -(D)-Phe-Pro-NH-4-amb(CO--CH₂ Ph)

MeSO₂ -(D)-Chg-Pro-NH-4-amb(CO--CF₃)

MeSO₂ -(D)-Chg-Pro-NH-4-amb(CHO)

MeSO₂ -(D)-Chg-Pro-NH-4-amb(COCH₂ OH)

MeSO₂ -(D)-Chg-Pro-NH-4-amb(COCONHCH₃)

MeSO₂ -(D)Phe-Pro-NH-(6-am)-3-pic

MeSO₂ -(D)Phe-Pro-NH-(5-am)-2-pic

MeSO₂ -(D)Phe-Pro-NH-(2-am-5-pyrim)methyl

MeSO₂ -(D)Phe-Pro-NH-(5-am-2-pyrim)methyl

MeSO₂ -(D)Phe-Pro-NH-(6-am-2-MeO)-3-pic

MeSO₂ -(D)Phe-Pro-NH-(2-am-5-pyraz)methyl

EtSO₂ -(D)Phe-Pro-NH-(6-am-2-F)-3-pic

CF₃ --CH₂ --SO₂ -(D)Phe-Pro-NH-(6-am-2-OH)-3-pic

n-BuSO₂ -(D)-Phe-Pro-NH-(6-am-2-BzO)-3-pic

n-BuSO₂ -(D)-Phe-Pro-NH-(6-am-2-OH)-3-pic

n-Octyl-SO₂ -(D)-Phe-Pro-NH-(6-am-2-i-PrO)-3-pic

Benzyl-SO₂ -(D)-Phe-Pro-NH-(6-am-2-OCH₂ COOM)e-3-pic

i-Propyl-SO₂ -(D)Phe-Pro-NH-(5-am-6-Cl)-2-pic

Phenyl-SO₂ -(D)Phe-Pro-NH-(5-am-3-MeO)-2-pic

2-Naphthyl-SO₂ -(D)Phe-Pro-NH-(5-am-3-OH)-2-pic

3-Pyridyl-SO₂ -(D)Phe-Pro-NH-(5-am-3-Me)-2-pic

2-Thienyl-SO₂ -(D)Phe-Pro-NH-(5-am-4-Me)-2-pic

N-Piperidinyl-SO₂ -(D)Phe-Pro-NH-(5-am-3-MeO)-2-pic

H₂ N--SO₂ -(D)Phe-Pro-NH-(5-am-4,6-Cl₂ -2-pyrim)methyl

Me₂ N--SO₂ -(D)Phe-Pro-NH-(2-am-4,6-(OH)₂ -5-pyrim)methyl

EtHN-SO₂ -(D)Phe-Pro-NH-(2-am-4,6-Cl₂ -5-pyrim)methyl

MeSO₂ -(D)Phe(4-OMe)-Pro-NH-(2-am-4,6-Me₂ -5-pyrim)methyl

MeSO₂ -(D)Phe(3-OMe)-Pro-NH-(5-am-4,6-(OH)₂ -2-pyrim)methyl

MeSO₂ -(D)Phe(4-Cl)-Pro-NH-(5-am-4,6-Me₂ -2-pyrim)methyl

MeSO₂ -(D)Cha-Pro-NH-(6-am)-3-pic

MeSO₂ -(D)Cha-Pyr-NH-(6-am)-3-pic

MeSO₂ -(D)Cha-Pro-NH-(5-am)-2-pic

MeSO₂ -(D)Cha-Pro-NH-(2-am-5-pyrim)methyl

MeSO₂ -(D)Cha-Pro-NH-(5-am-2-pyrim)methyl

MeSO₂ -(D)Cha-Pro-NH-(6-am-2-Me)-3-pic

MeSO₂ -(D)Cha-Pro-NH-(6-am-2-MeO)-3-pic

MeSO₂ -(D)Cha-Pro-NH-(6-am-2-Cl)-3-pic

MeSO₂ -(D)Cha-Pro-NH-(2-am-4,6-(MeO)₂ -5-pyrim)methyl

MeSO₂ -(D)Cha-Pro-NH-(5-am-4,6-(MeO)₂ -2-pyrim)methyl

MeSO₂ -(D)Cha-Pro-NH-(2-am)-5-pyraz

MeSO₂ -(D)Chg-Pro-NH-(6-am)-3-pic

MeSO₂ -(D)Chg-Pyr-NH-(6-am)-3-pic

MeSO₂ -(D)Chg-Pro-NH-(5-am)-2-pic

MeSO₂ -(D)Chg-Pro-NH-(2-am-5-pyrim)methyl

MeSO₂ -(D)Chg-Pro-NH-(5-am-2-pyrim)methyl

MeSO₂ -(D)Chg-Pro-NH-(6-am-2-Me)-3-pic

MeSO₂ -(D)Chg-Pro-NH-(6-am-2-MeO)-3-pic

MeSO₂ -(D)Chg-Pro-NH-(6-am-2-Cl)-3-pic

MeSO₂ -(D)Chg-Pro-NH-(2-am-4,6-(MeO)₂ -5-pyrim)methyl

MeSO₂ -(D)Chg-Pro-NH-(5-am-4,6-(MeO)₂ -2-pyrim)methyl

MeSO₂ -(D)Dpa-Pro-NH-(6-am-3)-pic

MeSO₂ -(D)Dpa-Pro-NH-(2-am-5-pyrim)methyl

MeSO₂ -(D)Dpa(4,4'-MeO)-Pro-NH-(6-am)-3-pic

MeSO₂ -(D)Dpa(4,4'-Cl₂)-Pro-NH-(6-am)-3-pic

MeSO₂ -(D,L)Phg(3,4-Cl₂)-Pro-NH-(5-am)-2-pic

MeSO₂ -(D,L)Phg(3,4-Cl₂)-Pro-NH-(5-am)-2-pyrim)methyl

MeSO₂ -(D)Tbg-Pro-NH-(6-am-2-MeO)-3-pic

MeSO₂ -(D)Asp(OH)-Pro-NH-(2-am-4,6-Cl₂ -5-pyrim)methyl

MeSO₂ -(D)Asp(OMe)-Pro-NH-(2-am-5-pyrim)methyl

MeSO₂ -(D)Asp(OMe)-Pro-NH-(6-am-2-Me)-3-pic

MeSO₂ -(D)Asp(OtBu)-Pro-NH-(6-am)-3-pic

MeSO₂ -(D)Asp(OtBu)-Pro-NH-(5-am-2-pyrim)methyl

MeSO₂ -(D)Phe-Aze-Pro-NH-(5-am)-2-pic

MeSO₂ -(D)Phe-Aze-Pro-NH-(2-am-4,6-(MeO)₂ -5-pyrim)methyl

MeSO₂ -(D)Phe-Pip-Pro-NH-(6-am)-3-pic

MeSO₂ -(D)Phe-Pip-Pro-NH-(2-am-5-pyrim)methyl

1-Naphthyl-SO₂ -Gly-Pro-NH-(5-am-)2-pic

1-Naphthyl-SO₂ -Gly-Pro-NH-(6-am-2-Me)-3-pic

HOOC--(CH₂)₃ --SO₂ -(D)Chg-Pro-NH-(6-am)-3-pic

HOOC--(CH₂)₃ -SO₂ -(D)Chg-Pro-NH-(5-am)-2-pic

MeSO₂ -(D)Ser(t-Bu)-Pro-NH-(6-am)-3-pic

MeSO₂ -(D)Ser(t-Bu)-Pro-NH-(5-am)-2-pic

HO₃ S-(D)Chg-Pro-NH-(6-am)-3-pic

MeSO₂ -TMSiA-Pro-NH-(6-am)-3-pic

The following substances may be mentioned as preferred:

1. MeSO₂ -(D)-(4-Methoxy)Phe-Pro-NH-(2-MeO)-4-amb

2. MeSO₂ -(D)-Chg-Pro-NH-4-amb(Me)

3. MeSO₂ -(D)-Cha-Pro-NH-(2-MeO)-4-amb

4. MeSO₂ -(D,L)-Dpa-Pro-NH-(2-MeO)-4-amb

5. MeSO₂ -(D)-Phe-Pro-NH-(6-am)-3-pic

6. MeSO₂ -(D)-Chg-Pro-NH-(6-am)-3-pic

7. MeSO₂ -(D)-Chg-Pro-NH-(5-am)-2-pic

8. MeSO₂ -(D)-Cha-Pyr-NH-(6-am)-3-pic

9. MeSO₂ -(D)-Chg-Pyr-NH-(6-am)-3-pic

10. HOOC--CH₂ --SO₂ -(D)-Cha-Pro-NH-(6-am)-3-pic

List of abbreviations:

AIBN: Azobisisobutyrodintrile sic!

am: Amidino

Ala: Alanine

4-amb: 4-Amidinobenzyl

Asp: Aspartic acid

Aze: Azetidinecarboxylic acid

Boc: tert-Butyloxycarbonyl

Bz: Benzyl

Cbz: Benzyloxycarbonyl

Cha: Cyclohexylalanine

Chg: Cyclohexylglycine

Cog: Cyclooctylglycine

Cpa: Cyclopentylalanine

(Cyclo)Leu: 1-Aminocyclohexanecarboxylic acid

DCM: Dichloromethane

Gly: Glycine

Hyp: Hydroxyproline

2-Ind: 2 Indolinecarboxylic sic! acid

Leu: Leucine

napme: Naphthylmethyl

NBS: N-Bromosuccinimide

Ph: Phenyl

Phe: Phenylalanine

2-Phi: 2-Perhydroindolecarboxylic acid

pic: Picolyl

Pip: Pipecolic acid

Pro: Proline

Pyr: 3,4-Pyrroline-2-carboxylic acid

pyrim: Pyrimidyl

pyraz: Pyrazinyl

Tbg: tert-Butylglycine

1-Tic: 1-Tetrahydroisoquinolinecarboxylic acid

3-Tic: 3-Tetrahydroisoquinolinecarboxylic acid

TMSiA: Trimethylsilylalanine

4-amb(R¹³) is the structure ##STR15##

The invention furthermore relates to the compounds of the formulae VII,VIII, IX and X ##STR16## where R¹, A, B and D have the stated meanings,and where the amidine functionality in formula VIII and in formula I canbe in mono- or diprotected form. The intermediates are novel, are usedfor preparing the compounds I and are valuable building blocks forsynthesizing serine protease inhibitors.

The structural fragment of the formula XI ##STR17## is novel and isvaluable as constituent of serine protease inhibitors and, inparticular, of thrombin inhibitors.

The compounds of the formula I may be used as such or in the form oftheir salts with physiologically tolerated acids. Examples of such acidsare: hydrochloric acid, citric acid, tartaric acid, lactic acid,phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleicacid, fumaric acid, maleic sic! acid, succinic acid, hydroxysuccinicacid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoicacid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.

The amidine functionality in the compounds I can be mono- or diprotectedby an amino protective group. Cbz and BOC sic! groups are particularlysuitable as protective group. The same applies to the amidinefunctionality in the compounds VIII.

The compounds I can be prepared starting from the α-amino acid H--A--OHor from the N-protected cyclic amino acid B--OH as shown in reactionschemes I and II. ##STR18##

In the above reaction schemes, R¹⁶ is H or C₁ -C₄ -alkyl, R¹⁷ is C₁ -C₄-alkyl, preferably methyl or t-butyl, R¹⁸ is CN or ##STR19## and P is aprotective group, preferably t-butoxycarbonyl (Boc) or benzyloxycarbonyl(Cbz).

Alternatively, the protected amino acids P--A--OH and H--B--OR¹⁷ can becoupled to give the dipeptide P--A--B--OR¹⁷ and then be reacted, afterelimination of P, with R¹ SO₂ Cl or, after elimination of R¹⁷, withcompounds of the formula VII or VIII, with the reaction sequence beingarbitrary.

R¹ --SO₂ --A--OH can also be coupled directly with

    H--B--NH--D--R.sup.18

to give the final product I or intermediate VII or IX.

If amidine-containing intermediates are used in protected form in theabove reaction sequences, the protective group(s) are eliminated at thefinal stage.

If R¹⁸ is an amide, lacuna! can be, after linkage to give

    P--A--B--NH--CH.sub.2 --D--CONH.sub.2

or

    R.sup.1 --SO.sub.2 --A--B--NH--CH.sub.2 --D--CONH.sub.2,

converted to the nitrile and therefrom further to the amidine.

The required coupling reactions are carried out under standardconditions of peptide chemistry (see M. Bodansky, A. Bodansky "ThePractice of Peptide Synthesis", Springer Verlag, (1084 sic!).

Boc protective groups are eliminated with HCl/dioxane or CF₃COOH/methylene chloride, and Cbz protective groups are eliminated byhydrogenolysis or with HF. Ester functionalities are hydrolyzed withNaOH or LiOH in an alcoholic solvent such as methanol or ethanol.t-Butyl esters are hydrolyzed with acids, eg. CF₃ COOH.

The reaction with the sulfonyl chlorides R¹ --SO₂ Cl in the presence ofan organic base such as triethylamine, pyridine orN,N-diisopropylethylamine takes place in organic solvents such as CH₂Cl₂, THF or DMF. In the case of free carboxyl groups, the reaction iscarried out in the presence of aqueous alkali metal hydroxide orcarbonate solutions.

The amidines are prepared from the nitrile precursors by the classicalPinner synthesis (R. Roger and D. G. Neilson, Chem. Rev. 61 (1961) 179)or, preferably, by a modified Pinner synthesis which takes place viaimino thioester salts as intermediates (H. Vieweg et al., Pharmazie 39(1984) 226). Catalytic hydrogenation of N-hydroxyamidines, which areobtainable by addition of hydroxylamine onto the cyano group, with RaneyNi or Pd/C in alcoholic solvents likewise results in amidines (B. J.Broughton et al., J. Med. Chem. 18 (1975) 1117).

The novel compounds can be used for the therapy and prophylaxis ofthrombin-dependent thromoembolic events such as deep vein thromboses,pulmonary embolisms, myocardial or cerebral infarcts and unstableangina, also for the therapy of disseminated intravascular coagulation(DIC). They are furthermore suitable for combination therapy withthrombolytics such as streptokinase, urokinase, prourokinase, t-PA,APSAC and other plasminogen activators to shorten the reperfusion timeand prolong the reocclusion time.

Further uses are the prevention of thrombin-dependent early reocclusionand later restenosis after percutaneous transluminal coronaryangioplasty, prevention of thrombin-induced proliferation of smoothmuscle cells, prevention of the accumulation of active thrombin in theCNS (eg. in Alzheimer's disease), control of tumors and prevention ofmechanisms leading to adhesion and metastasis of tumor cells.

Their particular advantage is that they are effective even after oraladministration.

The compounds according to the invention can be administered in aconventional way orally or parenterally (subcutaneously, intravenously,intramuscularly, intraperitoneally, rectally). Administration can alsotake place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient andon the mode of administration. As a rule, the daily dose of activeingredient per person is about 10-2000 mg on oral administration andabout 1-200 mg on parenteral administration. This dose can be given in 2to 4 single doses or once a day in depot form.

The novel compounds can be used in conventional solid or liquidpharmaceutical forms, eg. as uncoated or (film-)coated tablets,capsules, powders, granules, suppositories, solutions, ointments, creamsor sprays. These are produced in a conventional manner. The activeingredients can for this purpose be processed with conventionalpharmaceutical aids such as tablet binders, fillers, preservatives,tablet disintegrants, flow regulators, plasticizers, wetting agents,dispersants, emulsifiers, solvents, release-slowing agents, antioxidantsand/or propellant gases (cf. H. Sucker et al.: PharmazeutischeTechnologie, Thieme-Verlag, Stuttgart, 1978). The forms obtained in thisway normally contain the active ingredient in an amount of from 0.1 to99 percent by weight.

EXAMPLE 1 N-Methylsulfonyl-(D)-phenylalanyl-proline2-methoxy-4-amidinobenzylamide acetate

(a) 3-Nitro-4-methylbenzonitrile

399 g (2.56 mol) of 4-methylbenzonitrile were added over the course of90 min into 1 l of fuming nitric acid at -10° C. 1 h after the addition,the mixture was poured into 2.5 l of ice-water, whereupon a solidprecipitated and was separated off on a suction filter funnel and washedto neutral pH with water. The yield was 363 g (88%). ¹ H-NMR (CDCl₃ ; δin ppm): 8.3 (d,1H); 7.8 (dd, 1H); 7.5 (dd, 1H); 2.7 (s, 3H)

(b) 3-Amino-4-methylbenzonitrile

120 g of 3-Nitro-4-methylbenzonitrile were suspended in 1.2 l of EtOHand hydrogenated in the presence of 7 g of Pd/C (10%) with 50 l ofhydrogen at room temperature. After removal of the catalyst, the solventwas stripped off. 95 g of pure product were obtained (97%). ¹ H-NMR(DMSO-d⁶ ; δ in ppm): 7.1 (dd, 1H); 6.90 (d, 1H); 6.85 (dd, 1H); 5.35(s, 2H, NH2 sic!); 2.15 (s, 3H)

(c) 3-Hydroxy-4-methylbenzonitrile

A solution of 49.2 g (0.72 mol) of NaNO₂ in 217 ml of water was addeddropwise to 85 g (0.72 mol) of 3-amino-4-methylbenzonitrile in 1.8 l of6N HCl at 0-5° C. over the course of 0.5 h. The mixture was then stirredat 0-5° C. for a further 30 min and subsequently at the boiling pointfor 1 h. After the solution had cooled, the product was extracted withethyl acetate and, from this, in the form of the phenolate withice-cooled 5 N NaOH. The aqueous phase was then acidified to pH 3 with6N HCl, and the product was extracted with ethyl acetate. 41 g (43%)were obtained. ¹ H-NMR (DMSO-d⁶ ; δ in ppm): 10.3 (s, OH); 7.25 (dd,1H); 7.15 (d, 1H); 7.1 (dd, 1H); 2.20 (s, 3H)

(d) 3-Methoxy-4-methylbenzonitrile

15 g (0.11 mol) of 3-hydroxy-4-methylbenzonitrile dissolved in 30 ml ofDMF were added dropwise to a suspension of 0.11 mol of NaH in 30 ml ofDMF, and the mixture was stirred until no further H₂ evolution wasobserved. Then 10.6 ml (0.17 mol) of methyl iodide were added dropwise,and the mixture was stirred at room temperature for 1 h. The solutionwas poured into ice-water, and the product was extracted withether/ethyl acetate 7:1. After the solvent had been stripped off, theproduct began to crystallize slowly. 14.8 g (89%) were obtained. ¹ H-NMR(CDCl₃ ; δ in ppm): 7.2 (m, 2H); 7.02 (s, 1H); 3.85 (s, 3H); 2.25 (s,3H).

(e) 4-Bromomethy-3-methoxybenzonitrile sic!

14.7 g (0.1 mol) of 3-methoxy-4-methylbenzonitrile were dissolved in 210ml of 1,2-dichloroethane, brominated with 19.1 g (0.11 mol) of NBS inportions over the course of 1 h in the presence of catalytic amounts ofazobisisobutyronitrile at 82° C. and, after the addition was complete,stirred at 82° C. for a further 30 min. After addition of n-heptane,precipitated succinimide was removed, and the solvent was stripped off.The yield was 18.5 lacuna! (82%). ¹ H-NMR (DMSO-d⁶ ; δ in ppm): 7.60(dd, 1H); 7.50 (d, 1H); 7.40 (dd, 1H); 4.68 (s, 2H); 3.96 (s, 3H)

(f) 4-Phthalimidomethyl-3-methoxybenzonitrile

24.4 g (108 mol sic!) of 4-bromomethyl-3-methoxybenzonitrile, dissolvedin 125 ml of DMF, and 20.0 g of potassium phthalimide were stirred atroom temperature for 24 h and then at 50° C. for 1 h. The mixture waspoured into water, whereupon the product precipitated as solid. 21.5 g(68%) were obtained. ¹ H-NMR (DMSO-d⁶ ; δ in ppm): 7.9 (m, 4H); 7.5 (d,1H); 7.35-7.25 (m, 2H); 7.78 (s, 2H); 3.92 (s, 3H)

(g) 4-Aminomethyl-3-methoxybenzonitrile

10.6 ml of hydrazine hydrate were added to 21.2 g (73 mmol) of4-phthalimidomethyl-3-methoxybenzonitrile dissolved in 290 ml of THF,and the mixture was stirred at room temperature for 20 h. Then 180 ml of2H sic! HCl were added dropwise and, after 1.5 h, the solvent wascompletely stripped off. The residue was taken up in MTBE, extractedwith 1N HCl, adjusted to pH 9-10 with 2N NaOH and extracted withmethylene chloride. 8.0 g (68%) of product were obtained. ¹ H-NMR(DMSO-d⁶ ; δ in ppm): 7.55 (dd, 1H); 7.40 (dd, 1H; 7.37 (d, 1); 3.85 (s,3H); 3.70 (s, 2H); 2.5-1.6 (NH₂).

(h) Boc-proline 4-cyano-2-methoxybenzylamide

16.0 g of Boc-proline (50 mmol), dissolved in 80 ml of THF, were stirredwith 5.7 g of hydroxysuccinimide and 10.2 g of DCC in methylene chlorideat 0° C. for 30 min. Then 8.0 g (50 mmol) of4-aminomethyl-3-methoxybenzenenitrile sic! dissolved in 50 ml of THFwere added dropwise at 0° C., and the mixture was stirred at roomtemperature for 20 h. The solid was filtered off, the filtrate was mixedwith the same volume of ethyl acetate and washed with cooled 5% strengthNaHSO₄ solution and saturated NaCl solution. 11.5 g (65%) of productwere obtained. ¹ H-NMR (DMSO-d⁶ ; δ in ppm): 8.38 (m, NH); 7.50-7.35 (m,3H); 4.40-4.05 (m, 3H, N--CH₂ --Ar/N--CH--CO); 3.87 (s, OCH₃); 3.50-3.25(m, 2H, N--CH₂); 2.2.5-2.00 sic! (m, 1H); 1.90-1.65 (m, 3H); 1.40 and1.30 (2s; 9H)

(i) Proline 2-methoxy-4-cyanobenzylamide

11.4 g (31.7 mmol) of Boc-proline 2-methoxy-4-cyanobenzylamide weredissolved in 130 ml of methylene chloride and, at 0-5° C., saturatedwith HCI sic!. After 2 h the Boc group had been completely eliminated.The solvent was removed under reduced pressure, and the product was usedwithout further purification in the next reaction. ¹ H-NMR (DMSO-d⁶ ; δin ppm): 10.25 (s, 1H); 8.60 (s, 1H); 7.50 (d, 1H; 7.42 (dd, 1H); 7.39(d, 1); 4.40-4.20 (m, 3H); 3.88 (s, 3H); 3.20 (m, 2H); 2.35 (m, 1H);2.00-1.80 (m, 3H)

(j) Boc-(D)-4-methoxyphenylalanylproline 2-methoxy-4-cyanobenzylamide

1.55 g (5.25 mmol) of Boc-(D)-Phe-(4-OMe)-OH, 3.9 ml ofdiisopropylethylamine and 1.55 g (5.25 mmol) of proline2-methoxy-4-cyanobenzylamide hydrochloride were mixed at -5° C. with 4.4ml (5.9 mmol) of propanephosphonic anhydride (50% strength in ethylacetate) in 35 ml of methylene chloride and stirred at 0° C. for 1 h.The reaction mixture was washed successively with 1 N NaOH, 1 N HCl andsaturated brine and dried over Na₂ SO₄. The solvent was stripped off toleave 2.4 g of a solid. ¹ H-NMR (DMSO-d⁶ ; δ in ppm): 8.72 and 7.87 (t,2H); 7.42 (1H); 7.35 (m, 3H); 7.15 (d, 2H); 6.85 (d, 2H); 7.00+6.70 (2d) 1H; 4.40-4.10 (m, 4H); 3.85 (s, 3H; 3.70 (s, 3H); 3.05-2.55 (m, 4H);1.95-1.55 (m, 4H); 1.2 (s, 9H)

(k) (D)-4-Methoxyphenylalanylproline 2-methoxy-4-amidinobenzylamidedihydrochloride

The nitrile was converted by known processes (DE 4121947) via thethioamide stage into the amidine. Starting from the nitrile, 2.2 g ofthe thioamide were obtained. ¹ H-NMR (DMSO-d⁶ ; δ in ppm): 9.85 (s, 1H);9.45 (s, 1H); 8.65/7.85 (2 t, 1H); 7.55-6.65 (m, 7H, Ar--H); 4.40-4.10(m, 4H); 3.86/3.85 (2 s, 3H); 3.71/3.70 (2 s, 3H); 3.05-2.60 (m, 4H);2.10-1.55 (m, 4H); 1.35-1.10 (s, 9H)

Starting from 2.2 g of the thioamide and after reaction with methyliodide and methanolic ammonia solution and purification by columnchromatography on silica gel (mobile phase: DCM/MeOH 9:1), 1.7 g of theamidine were obtained as hydroiodide. ¹ H-NMR (DMSO-d⁶ ; δ in ppm): 9.28(s, 2H); 8.87 (s, 2H); 8.75/7.95 (st, 1H); 7.40-6.65 (m, 7H, Ar-H);4.45-4.10 (m, 4H); 3.90 (s, 3H); 3.70 (s, 3H); 3.7-3.4/3.0-2.6 (m, 4H);1.95-1.55 (m, 4H); 1.30/1.22 (2 s, 9H).

The amidine hydroiodide was converted into the amidine hydrochloride onan IRA 420 ion exchanger, then dissolved in 50 ml of methylene chlorideand saturated with HCI sic! at 0-5° C. After stirring for 1 h, thesolvent was stripped off. 1.0 g of the amidine was obtained asdihydrochloride. FAB-MS (M⁺) 453

¹ H-NMR (DMSO-d⁶, δ in ppm): 9.50 (5(broad) sic!, 2H), 9.25 (s(broad),2H), 8.85-8.65 (broad signal, 3H); 7.40 (s, 1H), 7.35 (d, 1H), 7.30 (d,1H), 7.15 (d, 2H), 6.90 (d, 2H), 4.35-4.10 (m, 4H), 3.85 (s, 3H), 3.75(s, 3H), 3.75-3.55 (m, 2H), 3.20-2.80 (m, 2 H), 1.90-1.40 (m, 4H)

(l) N-Methylsulfonyl-(D)-(4-methoxy)phenylalanylproline2-methoxy-4-amidinobenzylamide acetate

0.23 g (2 mmol) of methanesulfonyl chloride was added to a solution of0.9 g (2 mmol) of the above amidino sic! hydrochloride in 20 ml ofpyridine at 0° C., and the mixture was left to stir at room temperatureovernight. The residue after removal of the solvent by distillation waspurified by column chromatography (eluent: CH₂ Cl₂)methanol/50% strengthacetic acid, 45/5/1.5/. The eluate of pure fractions was distilled,adding toluene towards the end, and the residue was freeze dried. 0.5 gof acetate was obtained as white amorphous powder. FAB-MS: 531 (M⁺).

EXAMPLE 2 N-Methylsulfonyl-(D)-phenylalanylproline(α-methyl-4-amidino)benzylamide

(a) Benzophenone N-(p-cyanobenzyl) imine

270 g (2.0 mol) of anhydrous K₂ CO₃ were added to a solution of 150 g(0.8 mol) of 97% pure benzophenone imine and 144.8 g (0.74 mol) ofp-cyanobenzyl bromide in 450 ml of acetonitrile, and the mixture wasleft to stir at room temperature for 6 h. The inorganic salts werefiltered off with suction and then most of the solvent was removed bydistillation, 300 ml of water were added to the residue, and the mixturewas extracted several times with ethyl acetate. The organic phase waswashed 2× with water, dried over Na₂ SO₄ and evaporated to dryness.Digestion with ether resulted in 180 g of white crystals, melting point101-102° C.

(b) 1-(4-Cyanophenyl)ethylamine

20.7 g (0.07 mol) of benzophenone N-(p-cyanobenzyl)imine were addeddropwise to a solution of lithium diisopropylamide, prepared from 8.15 g(0.08 mol) of diisopropylamine and 48.3 ml (0.08 mol) of a 15% strengthsolution of butyllithium in hexane, in 100 ml of abs. tetrahydrofuran at-70° C., and the mixture was left to stir for 15 minutes. Then 9.94 g(0.07 mol) of methyl iodide were added dropwise, and the temperature ofthe reaction mixture was allowed to rise to room temperature. Afteraddition of 100 ml of water and several extractions with ether, theether phase was washed with 5% strength citric acid solution, 5%strength NaHCO₃ solution and water and was dried over Na₂ SO₄, and theether was distilled off. The residue was dissolved in 150 ml oftetrahydrofuran, 100 ml of 1 N HCl were added, and the mixture wasstirred at room temperature overnight. The tetrahydrofuran was distilledout of the reaction mixture under reduced pressure, the remaining acidphase was extracted several times with ether to remove the benzophenone,and then the acid phase was made alkaline with aqueous K₂ CO₃ solutionwhile cooling in ice, and the oily base was extracted with methylenechloride. The extract was dried over K₂ CO₃. 9.7 g (95%) of a yellowishoil remained after stripping-off the methylene chloride and were usedwithout further purification in the next reaction.

(c) Boc-(D)-phenylalanylproline (α-methyl-4-cyano)benzylamide

16.2 g of diisopropylamine and 22 ml (30 mmol) of propanephosphonicanhydride (50% strength solution in ethyl acetate) were added dropwiseto a solution of 3.65 g (25 mmol) of 1-(4-cyanophenyl)ethylamine and 9.1g (25 mmol) of Boc-D-Phe-Pro-OH in 150 ml of methylene chloride at -5°C. The mixture was then stirred for 2 h, during which the temperaturewas allowed to rise from -5° to 20° C. The organic phase was washed withwater, 5%. strength sodium bicarbonate solution and 5% strength citricacid solution, dried over Na₂ SO₄ and evaporated to dryness. A paleyellowish crystalline residue was obtained and was used without furtherpurification in the next reaction.

(D)-Phenylalanylproline (α-methyl-4-amidino)benzylamide dihydrochloride

4.1 g of the above compound and 4 ml of triethylamine were dissolved in40 ml of pyridine, saturated with H₂ S at 0° C., and left to stand atroom temperature overnight. A TLC check (CH₂ Cl₂ /MeOH, 9/1) showed thatconversion to thioamide was complete. For isolation, most of thepyridine was removed by distillation under reduced pressure, and theresidue was taken up in 250 ml of ethyl acetate and washed with brine,5% strength citric acid solution and NaHCO₃ solution. Drying and removalof the solvent by distillation afforded 4.1 g of pure crystallinethioamide.

The thioamide was dissolved in 150 ml of acetone and, after addition of7 ml of methyl iodide, left to stand at room temperature for 6 h. Theamorphous residue after stripping off the solvent was extracted bystirring with dry ether and then dried. The methyl S-thioimidatehydroiodide was dissolved in 50 ml of ethanol, 15 ml of 10% strengthammonium acetate solution were added, and the mixture was heated at 60°C. for 3 h. For isolation, the solvent was stripped off, the residue wasdissolved in 100 ml of CH₂ Cl₂, the insolubles were filtered off andthen the CH₂ Cl₂ was distilled off. Digestion with an ethylacetate/diethyl ether mixture removed the impurities soluble therein.The remaining iodide/acetate mixed salt was dissolved in acetone/water(3/2) and converted into the pure acetate using an IRA acetate ionexchange sic!, followed by freeze-drying. A white powder was isolated,melting point 110-115° C.

The above compound was dissolved in 70 ml of CH₂ Cl₂, and 80 ml ofHCl-saturated ethyl acetate were added. After a short time a precipitateseparated out and was completed by adding ether. The latter was filteredoff with suction, washed with ether until free of HCI sic! and driedunder reduced pressure. White crystals were obtained, melting point190-195° C., FAB-MS: 407 (M⁺).

(e) N-Methylsulfonyl-(D)-phenylalanylproline(α-methyl-4-amidino)benzylamide acetate

The title compound was obtained as white amorphous powder as for le.FAB-MS: 485 (M⁺).

EXAMPLE 3 N-Methylsulfonyl-(D)-cyclohexylalanylproline(2-methoxy-4-amidino)benzylamide

1.70 g (6.26 mmol) of Boc-(D)-Cha-OH were condensed as in Example 1jwith 1.85 g (6.26 mmol) of proline (2-methoxy-4-cyano)benzylamidehydrochloride (Example 1i) to give 2.7 g of Boc-(D)-Cha-Pro(2-MeO-4-CN)benzylamide, and subsequently the Boc protective group waseliminated with HCl gas in DCM. 2.0 g (4.45 mmol) of H-(D)-Cha-Pro(2-MeO-4-CN)benzylamide hydrochloride were reacted in 40 ml of DCM and8.9 mmol of diisopropylethylamine at 0° C. with 0.7 ml of methylsulfonylchloride to give 2.0 g of the corresponding sulfonamide. The nitrile wasconverted by a known process (DE 41 21 947) via the thioamide stage intothe amidine. Exchange of the amidine hydroiodide for the amidinehydroacetate (see Example 4b) resulted in 0.8 g of Me-SO₂ -(D)-Cha-Pro(2-methoxy-4-amidino)benzylamide, which was purified by columnchromatography as in Example 11. FAB-MS: (M+H)⁺ =496

EXAMPLE 4 N-Methylsulfonyl-(D,L)-diphenylalanylproline(2-methoxy-4-amidino)benzylamide

(a) Boc-(D,L)-Dpa-Pro (2-MeO-4-CN)benzylamide

6.0 g (17.6 mmol) of Boc-(D,L)-Dpa-OH and 5.2 g (17.6 mmol) of H-Pro(2-MeO-4-CN)-benzylamide hydrochloride were reacted as in Example 1j andsubsequently purified by column chromatography on silica gel (mobilephase: DCM/4.5% MeOH). 5.6 g of product were obtained.

¹ H-NMR (DMSO-d⁶ ; δ in ppm): 8.45 and 7.95 (1H, NH, (2 diastereomers orrotamers)), 7.5-6.9 (14H), 5.35-4.95 (m,1H), 4.5-4.1 (3H), 4.0-3.0 (3H),3.90 and 3.85 (s,3H) (2 diastereomers)), 2.1-1.1 (13H)

(b) Me-SO₂ -(D,L)-Dpa-Pro (2-MeO-4-amidino)benzylamide

3.55 g (6.0 mmol) of the Boc-protected compound (Example 4a) werecleaved in 30 ml of DCM with HCl gas to give 3.1 g of H-(D,L)-Dpa-Pro(2-MeO-4-CN)benzylamide hydrochloride, and 1.5 g (2.9 mmol) of thishydrochloride were stirred in 30 ml of DCM and 1.1 ml ofdiisopropylethylamine with 0.24 ml of methylsulfonyl chloride at 0° C.for 2 h. The organic phase was washed with 0.5 N HCl, water andsaturated NaCl solution and then dried, and the product was purified bycolumn chromatography on silica gel (mobile phase: DCM/5% MeOH). Thisresulted in 1.15 g of Me-SO₂ -(D,L)-Dpa-Pro (2-MeO-4-CN)benzylamide.1.15 g (2.1 mmol) of this nitrile were converted by a known process (DE41 21 947) via the thioamide stage into the amidine. There were obtained1.3 g of the thioamide and 0.95 g of the amidine hydroiodide, which wasconverted into the amidine hydroacetate on an ion exchanger (IRA 420).0.77 g of Me-SO₂ -(D,L)-Dpa-Pro (2-MeO-4-amidino)benzylamidehydroacetate (HPLC purity 95%) was obtained; FAB-MS: (M+H)⁺ =578

EXAMPLE 5 N-Methylsulfonyl-(D)-phenylalanylproline(6-amidino)-3-picolylamide acetate

(a) 2-Cyano-5-(azidomethyl)pyridine

14.5 g (0.07 mol) of trifluoroacetic anhydride dissolved in 20 ml ofmethylene chloride were added dropwise to a solution of 8.8 g (0.07mmol) of 2-cyano-5-(hydroxymethyl)pyridine (WO 83/01446) and 6.9 g oftriethylamine in 200 ml of methylene chloride at room temperature, andthe mixture was then stirred for 2 h. After removal of the methylenechloride by distillation, the residue was dissolved in a mixture of 50ml of toluene and 50 ml of dimethyl sulfoxide, 11.2 g (0.17 mol) ofsodium azide and 0.7 g of tetrabutylammonium bromide were added, and themixture was stirred at room temperature overnight.

The reaction mixture was poured into 300 ml of water and extractedseveral times with ether. After drying with Na₂ SO₄ and removal of theether by distillation, 6.8 g of yellowish crystals remained and wereused in the next reaction without further purification.

b) 2-Cyano-5-(aminomethyl)pyridine

The compound obtained in a) was dissolved in 45 ml of tetrahydrofuranand 1.2 ml of water and, while stirring, 11.2 g of triphenylphosphinewere added in portions. The reaction mixture was left to stand at roomtemperature overnight. After removal of the solvent by distillation, theresidue was taken up in 100 ml of ether, the precipitatedtriphenylphosphine oxide was filtered off with suction, and the filtratewas adjusted to pH 2 with ethereal hydrochloric acid. The precipitatedhydrochloride was filtered off with suction, washed with ether anddigested successively with toluene and hot isopropanol. 4.7 g (40%) ofhydrochloride were isolated, melting point 253-256° C. (decomposition).

c) Boc-(D)-phenylalanylproline (6-cyano)-3-picolylamide

8.12 g of diisopropylethylamine, and subsequently 11 ml (15 mmol) ofpropanephosphonic anhydride (50% strength solution in ethyl acetate),were added dropwise to a solution of 2.11 g (12.5 mmol) of2-cyano-5-(aminomethyl)pyridine and 4.5 g (12.5 mmol) ofBoc-D-Phe-Pro-OH in 70 ml of CH₂ Cl₂ at -5° C. The mixture was thenstirred for 2 h, allowing the temperature to rise from -5° to 20° C. Theorganic phase was washed with water, 5% strength sodium bicarbonate and5% strength citric acid solutions, dried over Na₂ SO₄ and evaporated todryness, a pale yellowish crystalline residue was obtained, meltingpoint 167-170° C., which was used in the next reaction without furtherpurification.

(d) N-Methylsulfonyl-(D)-phenylalanylproline (6-amidino)-3-picolylamideacetate

The above compound was dissolved in 100 ml of isopropanol and, afteraddition of a solution of 2.3 g of HCl in 20 ml of isopropanol, heatedat 50° C. for 5 h, during which the hydrochloride of the deprotectedcompound separated out. This was filtered off with suction and washedwith cold isopropanol until free of HCl.

2.5 g (6.5 mmol) of the above hydrochloride were suspended in 50 ml ofCH₂ Cl₂. Addition of 1.35 g (13.5 mmol) of triethylamine resulted in asolution to which, at 0 to 5° C., 0.7 g (6.1 mmol) of methanesulfonylchloride dissolved in 10 ml of CH₂ Cl₂ were added dropwise. The reactionmixture was stirred at room temperature for 5 h and then extracted byshaking with water, 5% strength citric acid and 5% strength NaHCO₃solutions. After drying over Na₂ SO₄ and removal of the solvent bydistillation, the viscous oily residue was recrystallized from an ethylacetate/ether mixture (1:1).

4.1 g of the above compound and 4 ml of triethylamine were dissolved in40 ml of pyridine, saturated with H₂ S at 0° C., and left to stand atroom temperature overnight. A TLC check (CH₂ Cl₂ /MeOH, 9/1) showed thatconversion to thioamide was complete. For isolation, most of thepyridine was removed by distillation under reduced pressure, and theresidue was taken up in 250 ml of ethyl acetate and washed with brine,5% strength citric acid solution and NaHCO₃ solution. Drying and removalof the solvent by distillation afforded 4.1 g of pure crystallinethioamide.

The thioamide was dissolved in 150 ml of acetone and, after addition of7 ml of methyl iodide, was left to stand at room temperature for 6 h.The amorphous residue after stripping off the solvent was extracted bystirring with dry ether and then dried. The methyl S-methylthioimidatehydroiodide was dissolved in 50 ml of ethanol, 15 ml of 10% strengthammonium acetate solution were added, and the mixture was heated at 60°C. for 3 h. For isolation, the solvent was stripped off, the residue wasdissolved in 100 ml of CH₂ Cl₂, the insolubles were filtered off andthen the CH₂ Cl₂ was distilled off. Digestion with an ethylacetate/diethyl ether mixture removed the impurities soluble therein.The remaining iodide/acetate mixed salt was dissolved in acetone/water(3/2) and converted into the pure acetate using an IRA acetate ionexchanger, followed by freeze-drying. A white amorphous powder wasisolated, melting point 128-137° C., FAB-MS: 473 (M+H⁺).

EXAMPLE 6 N-Methylsulfonyl-(D)-cyclohexylglycylproline(6-amidino)-3-picolylamide acetate

(a) Boc-(D)-cyclohexylglycylproline

29 g (0.113 mol) of Boc-(D)-cyclohexylglycine and 18.7 g (0.113 mol) ofproline methyl ester hydrochloride were suspended in 300 ml of CH₂ Cl₂and dissolved by dropwise addition of 58.3 g (0.45 mol) ofdiisopropylethylamine. After cooling to -15° C., 113 ml (0.147 mol) ofpropanephosphonic anhydride (50% strength solution in ethyl acetate)were added dropwise, and the mixture was stirred for 1 h.

After addition of 200 ml of water, the organic phase was separated offand washed with aqueous K₂ CO₃ solution, 0.5 N hydrochloric acid and 5%strength bicarbonate solution. After drying with Na₂ SO₄, the solventwas distilled off, the oily residue (41 g) was dissolved in 400 ml ofethanol, 120 ml of 1 N NaOH were added, and the mixture was stirred atroom temperature for 2 h.

After removal of the alcohol by distillation, the aqueous phase wasdiluted with water and extracted several times with methyl tert-butylether. The aqueous phase was acidified with KHSO₄ solution and extracted3× with CH₂ CL₂. After drying and distilling off the methylene chloride,the oily residue was crystallized from diisopropyl ether/n-hexane (1/3).28 g of white crystals were isolated, melting point 145-148° C.

b) Boc-(D)-cyclohexylglycylproline (6-cyano)-3-picolylamide

26.6 g (0.075 mol) of Boc-(D)-cyclohexylglycylproline and 12.7 g (0.075mol) of 6-cyano-3-picolylamine hydrochloride were suspended in 300 ml ofCH₂ Cl₂, and 47 g (0.364 mol) of diisopropylethylamine were added. Then,at -10° C., 66 ml of propanephosphonic anhydride (50% strength ethylacetate solution) were added dropwise, the mixture was stirred at 0° C.for 1 h, 200 ml of water were added, and the CH₂ Cl₂ phase was separatedoff. The organic phase was washed with 0.1 N sodium hydroxide solutionand water and then dried, and the solvent was distilled off. The residuewas taken up in 100 ml of ethyl acetate, whereupon crystallizationrapidly started and was completed by adding 150 ml of n-hexane. Afterfiltration with suction and drying, 31.4 g (89% of theory) of whitecrystals, melting point 150-151° C., were isolated.

(c) N-Methylsulfonyl-(D)-cyclohexylglycylproline(6-amidino)-3-picolylamide acetate

The protective group was eliminated from the above Boc compound as inExample 5d, reaction was carried out with methanesulfonyl chloride, andthe cyano group was converted into the amidine. The acetate was isolatedin the form of white crystals, melting point 250-256° C.(decomposition), FAB-MS: 465 (M+H⁺).

EXAMPLE 7 N-Methylsulfonyl-(D)-cyclohexylglycylproline(5-amidino)-2-picolylamide acetate

(a) 5-Carboxamido-2-picolylamine

3 g of Raney Ni were added to a solution of 3.5 g (24 mmol) of2-cyano-5-carboxamidopyridine in 80 ml of methanol and 20 ml ofconcentrated ammonia, and hydrogenation was carried out at roomtemperature. Uptake of hydrogen was complete after about 7 h.

The filtrate after the catalyst had been filtered off with suction wasconcentrated and the residue was dissolved in 20 ml of 2 N hydrochloricacid and 20 ml of methanol. Addition of 150 ml of ethyl acetate resultedin separation out of the hydrochloride, which was filtered off withsuction and dried (3.7 g). The free base melted at 198-202° C.

(b) 5-Cyano-2-picolylamine

41 g (0.22 mol) of 5-carboxamido-2-picolylamine were suspended in 150 mlof methanol and 300 ml of methylene chloride, cooled to 10° C., anddissolved by adding 150 ml of triethylamine. Then a solution of 47.6 g(0.22 mol) of (Boc)₂ O was added dropwise, and the mixture was stirredat room temperature for 4 h.

The residue after the solvent had been stripped off was mixed with asaturated K₂ CO₃ solution and extracted 5× with methylene chloride. Thecombined extracts were dried, and the solvent was distilled off, addingtoluene toward the end. 5.4 g of the residue were suspended in 40 ml ofdioxane and 15 ml of methylene chloride, 4.3 g of pyridine were added,and then, at 0° C., 5.2 g of trifluoroacetic anhydride were addeddropwise, resulting in a clear solution.

Addition of 100 ml of water was followed by extraction with ethylacetate, and the organic phase was washed with dilute citric acid,NaHCO₃ solution and water. A yellow oil (about 5 g) remained afterdrying and stripping off the solvent, and was dissolved in 15 ml ofisopropanol and 30 ml of ethyl acetate, and 35 ml of etherialhydrochloric acid solution were added. After standing overnight, theprecipitated hydrochloride was filtered off with suction and dried. 4 gof white crystals were isolated. Melting point 230-234° C.

(c) Boc-(D)-cyclohexylglycylproline (5-cyano)-2-picolylamide

Boc-(D)-cyclohexylglycine-proline sic! was coupled with5-cyano-2-picolylamine as in Example 6b to result in white crystals,melting point 128-129° C.

(d) N-Methylsulfonyl-(D)-cyclohexylglycylproline(5-amidino)-2-picolylamide acetate

The protective group was eliminated from the above Boc compound as inExample 5d, reaction was carried out with methanesulfonyl chloride, andthe cyano group was converted into the amidine. The acetate was isolatedin the form of white crystals, melting point 149-150° C.(decomposition),

FAB-MS: 465 (M+H⁺).

EXAMPLE 8 N-Methylsulfonyl-(D)-cyclohexylalanyl-3,4-dehydroproline(6-amidino)-3-picolylamide acetate

(a) Boc-3,4-dehydroproline (6-carboxamido)-3-picolylamide

5.0 g of Boc-3,4-dehydroproline (23.4 mmol) were suspended together with5.25 g of 6-carboxamido-3-picolylamine dihydrochloride and 32.1 ml ofdiisopropylethylamine (187 mmol) in 50 ml of CH₂ Cl₂ and, while stirringat 0 to 5° C., 23.5 ml of propanephosphonic anhydride (50% strengthsolution in ethyl acetate) were added dropwise. The mixture was thenstirred at room temperature overnight. The solution was diluted to 150ml with CH₂ Cl₂, extracted successively with 20% strength sodiumbisulfate solution and 5% strength citric acid solution, dried oversodium sulfate and concentrated in a rotary evaporator. The aqueousphases were back-extracted three times with CH₂ Cl₂, and the organicphase was dried, concentrated in a rotary evaporator and employedtogether with the main product without further purification in the nextreaction.

(b) H-3,4-dehydroproline (6-carboxamido)-3-picolylamide hydrochloride

The crude product from a) was dissolved in 100 ml of CH₂ Cl₂ and, afteraddition of 10 ml of 5M HCl in ether, stirred at room temperature for 2h (TLC check). The crude product after complete evaporation to drynessunder reduced pressure and codistillation with toluene under reducedpressure was recrystallized from 200 ml of ethanol. This resulted in5.03 g and, after concentration of the mother liquor, a further 0.3 g ofproduct. (80.4% of theory). Elemental analysis showed that the productwas in the form of the monohydrochloride.

(c) Boc-(D)-cyclohexylalanyl-3,4-dehydroproline(6-carboxamido)-3-picolylamide

5.06 g of Boc-(D)-cyclohexylalanine (18.66 mmol) were stirred togetherwith 5.28 g of H-3,4-dehydroproline (6-carboxamido)-3-picolylamidehydrochloride (18.66 mmol) and 9.55 ml of diisopropylethylamine (56mmol) in 75 ml of CH₂ Cl₂ and, at 0 to 5° C., 18.6 ml ofpropanephosphonic anhydride (50% strength solution in ethyl acetate)were added dropwise. The mixture was then stirred at room temperatureovernight, during which a precipitate separated out. After theprecipitate had been filtered off with suction and the solution had beenextracted five times with 25 ml of 5% strength citric acid each time(TLC showed no diisopropylethylamine left in the organic phase), theorganic phase was washed several times with saturated sodium bicarbonatesolution, dried over sodium sulfate and concentrated under reducedpressure. To minimize the propanephosphonic acid byproduct, the residuewas taken up in ethyl acetate, extracted several times with saturatedbicarbonate solution and then dried over sodium sulphate andconcentrated in a rotary evaporator. Yield 7.0 g of product assolidified foam (75% of theory).

(d) Boc-(D)-cyclohexylalanyl-3,4-dehydroproline (6-cyano)-3-picolylamide

7.0 g of Boc-(D)-cyclohexylalanyl-3,4-dehydroproline(6-carboxamido)-3-picolylamide (14 mmol) were dissolved together with9.5 ml of diisopropylethylamine (56 mmol) in 100 ml of methylenechloride, cooled to 0 to 5° C., and 3.5 ml of trifluoroacetic anhydride(25.2 mmol) were added dropwise. After stirring at room temperature for2 h, the precursor was completely converted (TLC check). The solutionwas then extracted three times with 25% strength sodium sulfatesolution, three times with saturated sodium bicarbonate solution andonce with saturated brine, dried over sodium sulfate and concentrated ina rotary evaporator. Yield: 6.6 g (98% of theory).

(e) Preparation of H-(D)-cyclohexylalanyl-3,4-dehydroproline(6-cyano)-3-picolylamide

6.6 g of Boc-(D)-cyclohexylalanyl-3,4-dehydroproline(6-cyano)-3-picolylamide (13.75 mmol) were dissolved in 15 ml ofisopropanol and, after addition of 12.5 ml of 4N isopropanolichydrochloric acid solution, stirred at 40° C. for 2 h (TLC check). Thereaction solution was concentrated under reduced pressure, the residuewas taken up in water, the solution was extracted three times withether, and the aqueous phase was adjusted to pH 9 with 20% strengthsodium hydroxide solution and extracted several times with CH₂ Cl₂. Theorganic phase was washed with saturated brine, dried over sodium sulfateand concentrated in a rotary evaporator to result in 4.3 g of product(82% of theory).

(f) Preparation ofmethylsulfonyl-(D)-cyclohexylalanyl-3,4-dehydroproline(6-cyano)-3-picolylamide

The compound was prepared as in Example 5d fromH-(D)-cyclohexylalanyl-3,4-dehydroproline (6-cyano)-3-picolylamide andmethanesulfonyl chloride. Yield: 95% of theory.

(g) Preparation ofmethylsulfonyl-(D)-cyclohexylalanyl-3,4-dehydroproline(6-amidino)-3-picolylamide

This compound was prepared as in Example 5d frommethylsulfonyl-(D)-cyclohexylalanyl-3,4-dehydroproline(6-cyano-3-picolyl)amide via the thioamide and methylS-methylthioamidate hydroiodide. A white amorphous powder was isolated.FAB-MS (M+H)⁺ =477

EXAMPLE 9 N-Methylsulfonyl-(D)-cyclohexylglycyl-3,4-dehydroproline(6-amidino)-3-picolylamide acetate

This compound was prepared as in Example 8. White amorphous powder,FAB-MS (M+H)⁺ =463.

EXAMPLE 10N-(Hydroxycarbonylmethylene)sulfonyl-(D)-cyclohexylglycylproline(6-amidino)-3-picolylamide

H-(D)-cyclohexylglycylproline (6-cyano)-3-picolylamide (Example 6b) wasreacted with methoxycarbonylmethylenesulfonyl chloride (preparationdisclosed in Tetrahedron Letters 30 (1989) 2869) to synthesize thecorresponding sulfonamide. The nitrile functionality was converted intothe amidine group via the thioamide stage by known processes (DE 41 21947).

The resultingN-(methoxycarbonylmethylene)sulfonyl-(D)-cyclohexylglycylproline(6-cyano)-3-picolylamide product was heated in a mixture of 4Nhydrochloric acid and dioxane at 80° C. to hydrolyze the esterfunctionality (TLC check), and then the solution was concentrated andthe residue was purified by HPLC on an RP column, and the aqueous phaseswere lyophilized; amorphous powder FAB-MS (M+H)⁺ 509.

We claim:
 1. A thrombin inhibitor compound of the formula I ##STR20## ora stereoisomer thereof or a salt thereof with a physiologicallytolerated acid, where the amidine functionality can be in mono- ordiprotected form and in which the substituents have the followingmeanings:R¹ is OH, C₁ -C₂₀ -alkyl, C₁ -C₃ -fluoroalkyl, C₃ -C₈-cycloalkyl, aryl-C₁ -C₁₀ -alkyl, aryl, hetaryl, R² OOC--(CH₂)_(n) or R³R² N, where R² and R³ are identical or different and are hydrogen, C₁-C₁₀ -alkyl, aryl, aryl-C₁ -C₁₀ -alkyl or together are a C₂ -C₇-alkylene chain to which an aryl or hetaryl radical can be fused orwhich can contain a hetero atom (O, S, NH or substituted N), and n is 1,2, 3 or 4, A: is an α-amino acid residue of the formula II ##STR21##where R⁴ is hydrogen, C₁ -C₈ -alkyl, C₃ -C₇ -cycloalkyl, aryl or aryl-C₁-C₃ -alkyl, R⁵ is hydrogen, C₁ -C₈ -alkyl, C₃ -C₇ -cycloalkyl or C₃ -C₇-cycloalkyl-CH₂ --, it being possible for a CH₂ group to be replaced byO, S, NR⁶, or bicycloalkyl-(CH₂)₀,1, adamantyl-(CH₂)₀₋₁, (CH₃)₃ Si--C₁-C₄ -alkyl, aryl or aryl-C₁ -C₃ -alkyl, hetaryl or hetaryl-C₁ -C₃-alkyl, if R⁴ is H, a C₁ -C₈ -alkyl radical in which a hydrogen atom isreplaced by SR⁶, OR⁶, CO--OR⁶ (R⁶ =hydrogen, C₁ -C₈ -alkyl or aryl-C₁-C₃ -alkyl) or CONR⁷ R⁸ (R⁷, R⁸ are identical or different and are H, C₁-C₄ -alkyl, C₃ -C₇ -cycloalkyl or together are a C₃ -C₆ -alkylenechain), or R⁴ and R⁵ together are a C₂ -C₆ -alkylene chain which maycontain a fused-on aryl radical, B: is a cyclic α-amino acid residue ofthe formula III ##STR22## where m is 2, 3 or 4, and a hydrogen on thering can be replaced by a hydroxyl or C₁ -C₃ -alkyl group and, if m is 3or 4, a CH₂ group in the ring can be replaced by oxygen, sulfur, NH orN--C₁ -C₄ -alkyl and/or two vicinal hydrogen atoms can be replaced by adouble bond or by a fused-on aromatic system or a methylene chain with4-6 carbon atoms, D: is a structural fragment of the formula IV, V or VI##STR23## where R⁹ is F, Cl, Br, NO₂, R¹⁵ O, R¹⁵ OOC, R¹⁵ OCH₂, R¹⁵NH--CO, R¹⁵ NH, R¹⁵ CONH or R¹⁵ OOCCH₂ O, where R¹⁵ is H, C₁ -C₆ -alkyl,benzyl or phenyl, R¹⁰, R¹¹ are H, C₁ -C₄ -alkyl or R¹⁵ O, where R⁹ andR¹⁰ or R¹¹ may together form a fused-on phenylene ring or an alkylenechain consisting of 3 to 5 carbon atoms, in which one or two carbonatoms can be replaced by oxygen, R¹² is H or C₁ -C₄ -alkyl, R¹³ is C₁-C₄ -alkyl, phenyl-C₁ -C₄ -alkyl, R¹⁵ CO, CF₃ CO, C₂ F₅ CO, R¹⁵ OCH₂,R¹⁵ OOC, R¹⁵ OCH₂ CO, R¹⁵ OOCCO or R¹⁵ NHCOCO, R¹⁴ is H, C₁ -C₄ -alkyl,F, Cl, Br, NO₂, R¹⁵ O, R¹⁵ OOC, R¹⁵ OCH₂, R¹⁵ CO, R¹⁵ CONH, R¹⁵ NH--COor R¹⁵ OOCCH₂ O, and W, X, Y, Z are CH or N, but at least one of theradicals W, X, Y or Z is N and the ring in VI can be substitued by 1 or2 of the following radicals: C₁ -C₄ -alkyl, OH, O--C₁ -C₄ -alkyl, CF₃,F, Cl, Br, S--C₁ -C₄ -alkyl, O(CH₂)_(n) COOR⁶ (n=1-4).
 2. A compound ofthe formula VII, VIII, IX or X, according to claim 1, ##STR24## whereR¹, A, B, D, W, X, Y and Z have the meanings stated in claim 1, andwhere the amidine functionality in formula VIII can be in mono- ordiprotected form.
 3. The thrombin inhibitory compound defined in claim1, which comprises a structural fragment XI, ##STR25## where D is astructural fragment of the formula IV, V or VI ##STR26## where R⁹ is F,Cl, Br, NO₂, R¹⁵ O, R¹⁵ OOC, R¹⁵ OCH₂, R¹⁵ NH--CO, R¹⁵ NH, R¹⁵ CONH orR¹⁵ OOCCH₂ O, where R¹⁵ is H, C₁ -C₆ -alkyl, benzyl or phenyl,R¹⁰, R¹¹are H, C₁ -C₄ -alkyl or R¹⁵ O, where R⁹ and R¹⁰ or R¹¹ may together forma fused-on phenylene ring or an alkylene chain consisting of 3 to 5carbon atoms, in which one or two carbon atoms can be replaced byoxygen, R¹² is H or C₁ -C₄ -alkyl, R¹³ is C₁ -C₄ -alkyl, phenyl-C₁ -C₄-alkyl, R¹⁵ CO, CF₃ CO, C₂ F₅ CO, R¹⁵ OCH₂, R¹⁵ OOC, R¹⁵ OCH₂ CO, R¹⁵OOCCO or R¹⁵ NHCOCO, R¹⁴ is H, C₁ -C₄ -alkyl, F, Cl, Br, NO₂, R¹⁵ O, R¹⁵OOC, R¹⁵ OCH₂, R¹⁵ CO, R¹⁵ CONH, R¹⁵ NH--CO, R¹⁵ OOCCH₂ O andW, X, Y, Zare CH or N, but at least one of the radicals W, X, Y or Z is N and thering in VI can be substituted by 1 or 2 of the following radicals: C₁-C₄ -alkyl, OH, O--C₁ -C₄ -alkyl, CF₃, F, Cl, Br, S--C₁ -C₄ -alkyl,O(CH₂)_(n) COOR⁶ (n=1-4).
 4. A method of preventing thrombin-dependentearly reocclusion and later restenosis after percutaneous transluminalcoronary angioplasty, thrombin-induced proliferation of smooth musclecells, accumulation of active thrombin in the CNS, and mechanismsleading to adhesion and metastasis of cancer cells, which methodcomprises administering to a patient an effective amount of a compoundof formula I as defined in claim
 1. 5. A method of treating deep veinthrombosis, pulmonary embolism, myocardial or cerebral infarct, unstableangina and disseminated intravascular coagulation, which methodcomprises administering to a patient an effective amount of the compoundof formula I as defined in claim 1.